{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T21:05:30Z","timestamp":1770066330513,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Disease Control and Prevention Administration Public Health Talent Training Support Project","award":["GJJKJ-2024-ZY"],"award-info":[{"award-number":["GJJKJ-2024-ZY"]}]},{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases","award":["ZDGWNLJS25-36"],"award-info":[{"award-number":["ZDGWNLJS25-36"]}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2302003"],"award-info":[{"award-number":["2021YFC2302003"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Coxsackievirus A16 (CVA16), a major etiological agent of hand, foot, and mouth disease, is increasingly contributing to neurological complications, with no vaccines or virus-specific antivirals currently available. To identify CVA16-restricting host factors, we investigated the role of the interferon-stimulated gene shiftless (SHFL), previously implicated in the control of other RNA viruses. Using CRISPR\u2013Cas 9, we generated SHFL knockout rhabdomyosarcoma cells and assessed viral replication, cytopathic effects, and replication stage dynamics. We evaluated disease progression and tissue injury in neonatal mice infected with a mouse-adapted CVA16 strain. SHFL expression was strongly induced during CVA16 infection and was inducible by exogenous interferon-\u03b2 treatment, and its loss markedly increased infectious virus production, accelerated early replication, and exerted severe cytopathic effects. In vivo, SHFL deficiency led to rapid weight loss, pronounced neurological signs, increased viral burden across multiple tissues, and uniform mortality, together with high viral loads and extensive pathological damage in the central nervous system, lungs, and skeletal muscle. Transcriptomic analyses revealed SHFL-dependent modulation of adhesion- and mitogen-activated protein kinase-related pathways. Overall, our results suggest SHFL as a key determinant of host resistance to CVA16, acting mainly at the post-transcriptional stage to limit viral spread and tissue injury, and highlight SHFL-linked pathways as promising host-directed antiviral targets.<\/jats:p>","DOI":"10.3390\/v18020192","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SHFL Post-Transcriptionally Restricts Coxsackievirus A16 In Vitro and In Vivo"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9323-7593","authenticated-orcid":false,"given":"Huijie","family":"Li","sequence":"first","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0660-8888","authenticated-orcid":false,"given":"Jichen","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1480-4438","authenticated-orcid":false,"given":"Wei","family":"Duan","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yucai","family":"Liang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4780-4826","authenticated-orcid":false,"given":"Qiang","family":"Sun","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"National Polio Laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"National Health Commission Key Laboratory of Microbial Genomics, National Health Commission Key Laboratory of Laboratory Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Beijing 102206, China"},{"name":"World Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6719-7155","authenticated-orcid":false,"given":"Jianfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases (NITFID), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease 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Health Organization Polio Reference Laboratory for the Western Pacific Region, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s12985-016-0578-3","article-title":"Characterization of VP1 sequence of coxsackievirus A16 isolates by bayesian evolutionary method","volume":"13","author":"Zhao","year":"2016","journal-title":"Virol. 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